We evaluated decreasing deferoxamine-induced urinary iron excretion during intensive chelation therapy in four children with thalassemia. Patients received daily intramuscular or subcutaneous therapy as well as intermittent intravenous infusions of high doses of DFO. Iron excretion fell by more than 80% in three patients and decreased by 45% in the fourth. Ferritin concentrations returned to normal or near normal values in all patients. Serum iron concentration and transferrin saturation steadily declined in one of four patients. Supplemental vitamin C was no longer required for normal vitamin C stores or maximum iron excretion in one patient after 26 months of chelation therapy. Interruption of chelation therapy was not followed by increased iron excretion after resumption of treatment with DFO. Decreasing DFO-induced iron excretion occurs during long-term, intensive chelation therapy, and may be the result of substantial reduction of excessive iron stores rather than of tachyphylaxis or transient depletion of an intracellular chelatable iron pool.